Ligase IV Syndrome (LIG4) is an extremely rare autosomal recessive disorder arising from mutations in the LIG4 gene, which encodes DNA ligase IV, a crucial component of the non-homologous end-joining (NHEJ) pathway responsible for repairing double-strand breaks (DSBs) in DNA.

The patient is a male child, born on July 11, 2017, diagnosed with constitutional severe aplastic anemia secondary to a LIG4 gene mutation, confirmed through genetic testing. This rare autosomal recessive condition is classified under ICD D61.0 and is associated with defective DNA repair mechanisms and immunodeficiency disorders. Over recent months, he has required monthly transfusions of red blood cells and platelets and exhibited persistent severe neutropenia (< 500 neutrophils/μL), increasing his susceptibility to opportunistic and severe infections. The clinical and laboratory findings, consistent with bone marrow failure, led to the recommendation of allogeneic hematopoietic stem cell transplantation (HSCT), the only potentially curative treatment in LIG4 deficiency. Between January and February 2025, the patient was admitted several times to Hospital Infantil Gonzaga for neutropenia-associated bacterial infections and transfusional support. Episodes of febrile neutropenia were managed with broad-spectrum antibiotics, including intravenous vancomycin and meropenem, with good clinical response. No allergies were reported. Given the severe bone marrow aplasia and intrinsic hypersensitivity of LIG4 deficiency patients to genotoxic agents, the medical team recommended unrelated donor HSCT with a reduced-intensity conditioning (RIC) protocol, based on recent clinical experience and established guidelines. Preparatory steps for transplantation included multidisciplinary evaluation, laboratory and imaging workup, admission to a protective environment, placement of a central venous catheter, and a conditioning regimen with fludarabine, thiotepa, and alemtuzumab. The treatment protocol also included antimicrobial prophylaxis (acyclovir, micafungin, sulfamethoxazole-trimethoprim), graft-versus-host disease (GVHD) prophylaxis (cyclosporine, mycophenolate mofetil, cyclophosphamide), adjuvant therapies (oral laser therapy and ursodeoxycholic acid), and continuous transfusion support. The planned hospitalization is approximately 60 days, followed by 4–6 months of intensive outpatient monitoring to assess for infections, GVHD, graft rejection, and chimerism. Given the severe bone marrow aplasia and intrinsic hypersensitivity of LIG4 deficiency patients to genotoxic agents, the medical team recommended unrelated donor HSCT with a reduced-intensity conditioning (RIC) protocol, based on recent clinical experience and established guidelines. Preparatory steps for transplantation included multidisciplinary evaluation, laboratory and imaging workup, admission to a protective environment, placement of a central venous catheter, and a conditioning regimen with fludarabine, thiotepa, and alemtuzumab.

This case highlights the clinical complexity of LIG4 syndrome and the value of personalized transplant strategies. Genetic counseling and early screening are essential in managing inherited bone marrow failure syndromes.